Omineca Herald, May, 10, 1933

Context. In central hypothyroidism (CeH) free thyroxine (FT4) concentrations are low while TSH concentrations may be low, normal or even slightly elevated due to reduced bioactivity. Congenital CeH (CCeH) may be isolated or part of multiple pituitary hormone deficiency (MPHD). Objective. To test our hypotheses that (1) TSH concentrations have a more U-shaped distribution in children with CCeH compared to children with a normally functioning hypothalamic-pituitary-thyroid-axis, and (2) TSH concentrations in children with CCeH with MPHD are higher compared to children with isolated CCeH. We also studied whether FT4 levels are helpful in distinguishing CCeH from mild primary CH (CH-T). Methods. Dutch neonatal screening TSH and first diagnostic TSH and FT4 were analyzed of all children diagnosed with permanent CCeH between 1995 and 2012. Controls were children with TBG deficiency. FT4 concentrations in CCeH were compared to those in CH-T with TSH-values in the same range as those of CCeH. Results. We studied 120 children with CCeH (isolated CCeH, N=50; MPHD, N=70) and 350 controls. Screening TSH concentrations were not significantly different (p =0.055) but diagnostic TSH values were significantly different between the CCeH group and the control group (p=0.037). TSH was significantly higher in MPHD compared to isolated CCeH (p=0.004). FT4 concentrations were significantly lower in CCeH compared to mild CH-T (p<0.0005). Conclusion. TSH values in CCeH have a more U-shaped distribution compared to controls with the TSH concentrations in CCeH with MPHD. FT4 levels were significantly lower in CCeH compared to CH-T. Chemicals/CAS: thyrotropin, 9002-71-5; thyroxine, 7488-70-

Pasireotide treatment for severe congenital hyper-insulinism due to a homozygous ABCC8 mutation

ABCC8 and KCJN11 mutations cause the most severe diazoxide-resistant forms of congenital hyperinsulinism (CHI). Somatostatin analogues are considered as secondline treatment in diazoxide-unresponsive cases. Current treatment protocols include the first-generation somatostatin analogue octreotide, although pasireotide, a second-generation somatostatin analogue, might be more effective in reducing insulin secretion. Herein we report the first off-label use of pasireotide in a boy with a severe therapy-resistant form of CHI due to a homozygous ABCC8 mutation. After partial pancreatectomy, hyperinsulinism persisted; in an attempt to prevent further surgery, off-label treatment with pasireotide was initiated. Short-acting pasireotide treatment caused high blood glucose level shortly after injection. Long-acting pasireotide treatment resulted in more stable glycemic control. No side effects (e.g., central adrenal insufficiency) were noticed during a 2-month treatment period. Because of recurrent hypoglycemia despite a rather high carbohydrate intake, the boy underwent near-total pancreatectomy at the age of 11 months. In conclusion, pasireotide treatment slightly improved glycemic control without side effects in a boy with severe CHI. However, the effect of pasireotide was not sufficient to prevent near-total pancreatectomy in this case of severe CHI

Mutations in IRS4 are associated with central hypothyroidism

Diabetes mellitus: pathophysiological changes and therap

Mutations in IRS4 are associated with central hypothyroidism

Background: Four genetic causes of isolated congenital central hypothyroidism (CeH) have been identified, but many cases remain unexplained. We hypothesised the existence of other genetic causes of CeH with a Mendelian inheritance pattern. Methods: We performed exome sequencing in two families with unexplained isolated CeH and subsequently Sanger sequenced unrelated idiopathic CeH cases. We performed clinical and biochemical characterisation of the probands and carriers identified by family screening. We investigated IRS4 mRNA expression in human hypothalamus and pituitary tissue, and measured serum thyroid hormones and Trh and Tshb mRNA expression in hypothalamus and pituitary tissue of Irs4 knockout mice. Results: We found mutations in the insulin receptor substrate 4 (IRS4) gene in two pairs of brothers with CeH (one nonsense, one frameshift). Sequencing of IRS4 in 12 unrelated CeH cases negative for variants in known genes yielded three frameshift mutatio

Disease characteristics of MCT8 deficiency : an international, retrospective, multicentre cohort study

Background Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency. Methods We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1·5 years and between patients who were or were not underweight by age 1–3 years (defined as a bodyweight-for-age Z score <–2 SDs or <5th percentile according to WHO definition). Other objectives were to assess neurocognitive function and outcomes, and clinical parameters including anthropometric characteristics, biochemical markers, and neuroimaging findings. Findings Between Oct 14, 2014, and Jan 17, 2020, we enrolled 151 patients with 73 different MCT8 (SLC16A2) mutations. Median age at diagnosis was 24·0 months (IQR 12·0-60·0, range 0·0-744·0). 32 (21%) of 151 patients died; the main causes of mortality in these patients were pulmonary infection (six [19%]) and sudden death (six [19%]). Median overall survival was 35·0 years (95% CI 8·3–61·7). Individuals who did not attain head control by age 1·5 years had an increased risk of death compared with patients who did attain head control (hazard ratio [HR] 3·46, 95% CI 1·76–8·34; log-rank test p=0·0041). Patients who were underweight during age 1–3 years had an increased risk for death compared with patients who were of normal bodyweight at this age (HR 4·71, 95% CI 1·26–17·58, p=0·021). The few motor and cognitive abilities of patients did not improve with age, as evidenced by the absence of significant correlations between biological age and scores on the Gross Motor Function Measure-88 and Bayley Scales of Infant Development III. Tri-iodothyronine concentrations were above the age-specific upper limit in 96 (95%) of 101 patients and free thyroxine concentrations were below the age-specific lower limit in 94 (89%) of 106 patients. 59 (71%) of 83 patients were underweight. 25 (53%) of 47 patients had elevated systolic blood pressure above the 90th percentile, 34 (76%) of 45 patients had premature atrial contractions, and 20 (31%) of 64 had resting tachycardia. The most consistent MRI finding was a global delay in myelination, which occurred in 13 (100%) of 13 patients. Interpretation Our description of characteristics of MCT8 deficiency in a large patient cohort reveals poor survival with a high prevalence of treatable underlying risk factors, and provides knowledge that might inform clinical management and future evaluation of therapies

Congenital central hypothyroidism:Diagnostics and pathogenesis

The focus of the studies described in this thesis lies on diagnostics and pathogenesis of con- genital central hypothyroidism. The importance of, and difficulties in diagnosing congenital central hypothyroidism are emphasized. In addition, the complex polygenic etiology of congenital central hypothyroidism within the framework of multiple pituitary hormone deficiencies (specifically pituitary stalk interruption syndrome) is highlighted

The severity of congenital hypothyroidism of central origin should not be underestimated

Congenital hypothyroidism (CH) may be of thyroidal (CHT) or central origin (CHC). Worldwide, most neonatal screening programs are TSH based and effectively detect CHT. Only a few screening programs measure total or free T4 and TSH simultaneously or stepwise, enabling detection of CHT as well as CHC. A frequently used argument against screening for CHC is its presumed mild hypothyroid character. In the recently published European Society for Paediatric Endocrinology (ESPE) CH consensus guidelines on screening, diagnosis and management, severity of CH is classified based on initial free T4 (FT4) concentrations. Objective: To assess disease severity of CHC compared to CHT in a Dutch cohort of CH patients. Methods: Pre-treatment FT4 concentrations were analyzed in all children with CH detected by the Dutch neonatal T4+TSH+T4-binding-globulin (TBG) screening between 1995 and 2011. Disease severity was classified using the FT4-based ESPE classification. Results: Between 1995 and 2011, 1288 children were diagnosed with CH. Data of 1200 (CHC: 143, CHT: 1057) were available for analysis. Based on FT4 concentrations 4 children with CHC (2.8%) had severe CH, 75 (52.4%) moderate and 64 (44.8%) mild. In the CHT group 280 children (26.5%) had severe CH, 341 (32.3%) moderate and 436 (41.2%) mild. Discussion:/Conclusion /Conclusion: Our results indicate that, based on initial FT4-values, severe CH was much more prevalent in CHT compared to CHC. However CHC itself should not be considered as only mild since more than half of CHC patients have moderate CH with initial FT4 below 10 pmol/l

Clinical and genetic characteristics of Dutch children with central congenital hypothyroidism, early detected by neonatal screening

Objective: To evaluate clinical characteristics of patients with central congenital hypothyroidism (CH), detected in the Dutch neonatal screening program. This included patients with isolated central CH but the majority have multiple pituitary hormone deficiencies (MPHD). Design: Nationwide, cross-sectional study. Methods: Data was collected on clinical characteristics, endocrine tests and neuroimaging of central CH patients, detected by the Dutch neonatal screening and born between 1 January 1995 and 1 January 2015. Height and pubertal status were assessed during a study visit. Isolated central CH patients without a confirmed genetic diagnosis were offered genetic (re-)testing. Results: During the 20-year period 154 central CH patients were detected (incidence of permanent central CH 1:25 642). After excluding deceased (15), severe syndromic (7) and transient patients (6), 92 of 126 eligible patients were included (57 MPHD; 79% male). Sixty-one patients (50 MPHD) had been hospitalized before screening results were reported, but central CH was diagnosed on clinical grounds in only three of them (5%). MRI abnormalities consistent with pituitary stalk interruption syndrome were seen in 50 (93%) MPHD patients. Among isolated central CH patients, 27 (84%) had an IGSF1, TBL1X or IRS4 gene variant (53, 16 and 16%, respectively). Conclusion: Many patients with central CH have neonatal health problems, especially MPHD patients. Despite hospital admission of two-thirds of patients, almost none were diagnosed clinically, but only after the notification of an abnormal screening result was received. This indicates that central CH, especially if isolated, is an easily missed clinical diagnosis